Abstract 3275: Reprogramming of MDSCs by ST316, a clinical peptide antagonist of b-Catenin/BCL9, enhances anti-tumor immuno- and chemotherapy

Abstract Myeloid-derived suppressor cells (MDSCs) are a diverse group of immune cells that play critical roles in mediating immune-suppression. They are often associated with poor responses in various cancer types and represent an attractive target for immunotherapy. Challenges in defining the genetic dependencies of MDSCs have hindered the development of effective therapeutic strategies aimed at targeting them. The Wnt/β-catenin signaling pathway is a key oncogenic driver that has been implicated in immune-exclusion, although additional roles in immune-suppression remain unclear. ST316 is a clinical-stage peptide antagonist of the interaction between β-catenin and its co-activators, BCL9 and BCL9L. Currently, ST316 is being evaluated in a Phase 2 study (NCT05848739) in patients with advanced colorectal cancer (CRC) in combination with standard-of-care agents. We demonstrated in a Phase 1 dose escalation study that ST316 suppresses MDSC expansion in the peripheral blood of treated patients and corroborated these findings in non-clinical CRC murine models. Here, we characterize the role of the Wnt/β-catenin/BCL9 pathway in MDSC programming and investigate the mechanism by which ST316 reduces MDSC expression and immuno-suppressive activity. Transcriptional profiling of MDSCs from tumor-bearing mice indicates that β-catenin and other Wnt pathway components are highly expressed in these cells. Our findings indicate that exposure to ST316 reduces the expression of receptor systems linked to MDSC-mediated T-cell suppression, thereby activating T-cell responses in vivo. In combination studies, ST316 significantly enhances the anti-tumor efficacy of anti-PD-1 immunotherapy and standard-of-care chemotherapies for advanced CRC such as FOLFIRI. Moreover, while anti-PD-1 and FOLFIRI alone each resulted in expansion of immunosuppressive MDSCs, combination with ST316 prevented this expansion. Our results reveal a novel role for Wnt/β-catenin signaling in MDSC biology and demonstrate that ST316 can suppress the increase of therapy-driven MDSCs in vivo. These data suggest that therapeutically targeting the BCL9/β-catenin interaction may be an effective strategy to enhance both chemotherapy and immunotherapy in Wnt-driven tumors that respond poorly to monotherapy. Citation Format: Claudio Scuoppo, Julia Diehl, Ricardo Ramirez, Barry J. Kappel, Abi Vainstein-Haras, Jim A. Rotolo. Reprogramming of MDSCs by ST316, a clinical peptide antagonist of b-Catenin/BCL9, enhances anti-tumor immuno- and chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3275.